Atypical Hyperplasia as a Predictor of Future Breast Cancer: Focus on Chemoprevention and Screening


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Otis Brawley, MD

Atypical hyperplasia of the breast has “special importance as a predictor of future breast cancer,” according to a special report in The New England Journal of Medicine.1 That special importance is based on the high incidence of atypical hyperplasia—found in around 10% of the 1 million breast biopsies with benign results performed annually in the United States—and the high risk—“with a cumulative incidence of breast cancer approaching 30% at 25 years of follow-up.”

Because of the incidence, high risk, and “availability of effective breast cancer prevention strategies, atypical hyperplasia is the benign breast diagnosis that is the most important to act on clinically,” the authors averred. The suggested clinical actions are more intensive screening using magnetic resonance imaging (MRI) and chemoprevention using selective estrogen-receptor modulators and aromatase inhibitors.

High Risk Not Widely Recognized

The two types of atypical hyperplasia—atypical ductal hyperplasia and atypical lobular hyperplasia—“occur with equal frequency and confer similar risks of later breast cancer”; they also are referred to together in the report as atypical hyperplasia. The high cumulative incidence approaching 30% at 25 years “is not widely recognized, and thus women with atypical hyperplasia are not included in many high-risk guidelines,” the authors acknowledged.

A longitudinal cohort study considered a landmark study reported in 1985 and found that women with atypical hyperplasia had a 4.4 relative risk for later invasive breast cancer.2 Other studies reported since then have consistently found a fourfold increase in relative risk.

“More recent data on absolute risk from the Nashville Breast Cohort (unpublished data) and another large cohort at the Mayo Clinic confirm the cumulative high risk of breast cancer among women with atypical hyperplasia. Specifically, 25 years after a biopsy that showed atypical hyperplasia, breast cancer (either in situ or invasive) developed in 30% of the women in the Mayo Clinic cohort. Similar updated results were obtained in the Nashville Breast Cohort, with either in situ or invasive disease developing in 27.5% of participants (unpublished data),” according to the report.

Potential Impact on Screening Guidelines

These newer data show a level of risk that meets the current standard for MRI screening in guidelines for breast cancer screening for high-risk women. “Those guidelines say that a lifetime risk of 20% to 25% is a high enough risk to justify MRI for screening for breast cancer,” study coauthor Amy C. Degnim, MD, of the Department of Surgery, Mayo Clinic, Rochester, Minnesota, told The ASCO Post. A “caveat” to those recommendations, Dr. Degnim noted, is that  “women with atypical hyperplasia were not thought to have a risk high enough to warrant MRI screening. Now our data show that their breast cancer risk is high enough to justify MRI screening.”

“They’ve got a legitimate point,” American Cancer Society (ACS) Chief Medical Officer Otis Brawley, MD, is quoted as saying in a Reuter’s health article3 about the report. That article also reported that Dr. Brawley said women with atypical hyperplasia probably should be getting an MRI.

Currently, the ACS “recommends breast MRI as an adjunct to mammography for high-risk patients who have a lifetime risk of approximately 20% to 25% or greater,” the report authors pointed out. “It is my understanding that the American Cancer Society is going to be looking at updating those guidelines,” Dr. Degnim said.

The American College of Radiation “cites a lifetime risk of only 15% to 20% among women with atypical hyperplasia and thus concludes that the usefulness of screening these women with MRI is ‘still in question,’” the report authors noted. The National Comprehensive Cancer Network (NCCN) recommends annual MRI screening “for women with a lifetime risk greater than 20%, as defined by models that are dependent largely on family history,” the authors added, but “for women with atypical hyperplasia specifically, they state that there is insufficient evidence to make recommendations for or against MRI screening.”

‘Scientifically Justified’

Whether or not guidelines are revised to incorporate a recommendation to use MRI to screen women diagnosed with atypical hyperplasia, “physicians should be discussing it with their patients as a possibility,” Dr. Degnim advised. “If a woman feels that her risk is high enough and she is interested in pursuing MRI, I think that based on our study, there is a very strong case to argue that it is scientifically justified.”

Further Stratification of Risk

Existing risk prediction models, such as the Breast Cancer Risk Assessment Tool (BCRAT) and the International Breast Cancer Intervention Study (IBIS) model, perform poorly among women with atypical hyperplasia, according to the report. The authors advised using instead cumulative risk data to counsel women about their risk for breast cancer.

Knowing the number of foci of atypical hyperplasia can further stratify the risk. “We found that for women who had three or more foci of atypical hyperplasia, at 25 years, their risk was 47%, so almost 50%, or about a 2% risk per year,” Dr. Degnim said.

The number of foci is not always known; it “has not been a standard item found in pathology reports,” Dr. Degnim noted. “The current expectation,” she said, is that the pathologist’s report would include whether or not there is atypical hyperplasia or other abnormalities. “Our hope is that this report may help to drive the field to start including the number of foci as a standard part of the pathology report,” Dr. Degnim said.

To Excise or Not to Excise

“If a woman has a needle biopsy and the pathologist reports one focus of atypia, that does not mean the patient may not have more; to get that information, you would need to excise the site of atypia, get a little more tissue, and find out if it really is just one focus or more,” Dr. Degnim said. She noted that it is sometimes possible to detect multiple foci with a needle biopsy.

“Generally, our standard for atypical ductal hyperplasia is to re-excise the site surgically, because about 15% of the time, those women may actually have cancer there; in order to find that out, we have to excise it,” Dr. Degnim said. If excision revealed more sites of atypical hyperplasia, that “would help us to estimate how high the woman’s breast cancer risk is for the long term,” she added.

“For the lobular type of atypical hyperplasia, more recent data indicate that it may not need to be excised surgically. When atypical lobular hyperplasia is found on a needle biopsy, as long as the findings are all concordant—what is on the mammogram looks consistent with atypical lobular hyperplasia, does not look worrisome for a cancer—it is safe not to excise that surgically and just to follow it,” Dr. Degnim said. “It might be the case that there is one focus of atypical lobular hyperplasia on a core biopsy, and we think there is a low risk of cancer, so the patient does not have it surgically excised. She may have more foci of atypical lobular hyperplasia there, which would help us to predict her breast cancer risk long term.

But then you have to weigh that balance: Is it worth doing an operation just to get that information? Currently, probably we would say no. But that would be something to discuss with individual patients. Then it could be handled based on their priorities. If it is very important for them to have that additional information, a surgical biopsy could be done.”

Prophylactic Mastectomy Not Generally Indicated

Atypical hyperplasia is “generally not an indication” for prophylactic mastectomy, according to the report. “Ultimately, it is really a matter of a woman’s choice,” Dr. Degnim stressed. “However, we would favor other approaches, such as prevention medications and MRI screening rather than mastectomy. The potential psychological effects, as well as the physical effects—how mastectomies change a woman’s body and what impact that will have on her—can be serious. Because prophylactic mastectomy “is an irrevocable step,” before we would do that, there would be thorough counseling and time for consideration of that decision,” Dr. Degnim said.

“This is why it is important to be able to estimate breast cancer risk for each individual woman with atypical hyperplasia. Although the majority of all women with atypical hyperplasia do not get breast cancer, the risk is quite high in some individuals. At 25 years, the risk of breast cancer for women with three or more foci of atypical hyperplasia was 47%. For women with BRCA mutations, the risk was generally quoted as between 50% and 80%,” Dr. Degnim said. “Not all women with atypical hyperplasia appear to have the same level of risk, but for some women who might be in that high-risk group of three or more foci of atypia, their risk level appears to be similar to that of a BRCA carrier. And bilateral mastectomy is considered for women who have a risk that high. So it is a possibility,” Dr. Degnim said, although chemoprevention is usually favored over prophylactic mastectomy.

Chemoprevention Medications

Several statements in the special report support the use of selective estrogen-receptor modulators and aromatase inhibitors to prevent breast cancer in women with atypical hyperplasia. They include reported results from several large breast cancer chemoprevention trials, as well as subgroup analyses showing relative risk reductions ranging from 41% to 79%, “which suggested an even greater benefit than in the total population treated with active agents in those trials,” the authors noted.

“The high level of estrogen-receptor expression in the large majority of breast cancers that develop in women with atypical hyperplasia provide an additional rationale for the use of antiestrogen therapy for prevention,” the authors added. With a cumulative risk of approximately 1% per year, women with atypical hyperplasia “clearly meet” the ASCO guideline, stating “that for women with a 5-year projected absolute risk of breast cancer of 1.7% or higher, the use of a chemopreventive agent should be discussed,” the authors pointed out. 

Infrequently Prescribed, Infrequently Used

Chemopreventive agents, however, “are infrequently prescribed and infrequently used,” according to the report. One of the reasons cited for infrequent prescribing is that “physicians feel insufficiently informed about these agents.”

“That’s a big challenge,” Dr. Degnim noted, adding that education is a key step in meeting that challenge. “We are hoping that publishing this article will help to raise awareness and better inform providers.”

Challenges for patients often involve the perception of side effects. Although some side effects do occur, they occur much less frequently than most women think. Side effects include venous thromboembolism associated with all selective estrogen-receptor modulators, an increased risk of endometrial cancer associated with tamoxifen (but not other selective estrogen-receptor modulators), and vasomotor symptoms in many women taking selective estrogen-receptor modulators or aromatase inhibitors.

“We hope that having more accurate assessment of an individual woman’s risk will help patients to benefit from prevention medications,” Dr. Degnim said. Knowing that their risk approaches 30% at 25 years “may motivate them more strongly to stay on their risk-reduction medication.” ■

Disclosure: Dr. Degnim reported no potental conflicts of interest.

References

1. Hartmann LC, Degnim AC, Santen RJ, et al: Atypical hyperplasia of the breast—risk assessment and management options. N Engl J Med 372:78-89, 2015.

2. Dupont WD, Page DL: Risk factors for breast cancer in women with proliferative breast disease. N Engl J Med 312:146-151, 1985.

3. Emery G: Suspicious breast mass may pose greater risk than previously thought. Reuters January 1, 2015. Available at http://in.reuters.com/article/2014/12/31/us-breast-biopsy-cancer-risk-idINKBN0K918A20141231. Accessed February 6, 2015.


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